This program represents a multidisciplinary approach save towards developing new prognostic indicators for breast cancer. We suggest that the variable course of breast cancer is in large part the result of fundamental differences among patients in the cellular biology of the malignant epithelium and its reactive stroma. Our rationale is that recent advances in molecular and cell biology using model systems are ready to be applied directly to the problem. The research projects will concentrate on four areas: 1) oncogene and receptor activation, by developing new assays to improve the prognostic specificity of c-erbB-2 proto-oncogene overexpression and estrogen receptor content based on mechanisms mediating the abnormal expression of these genes; 2) genetic aberrations, by relating prognosis to overall level of genetic aberrations and by searching for new genes whose aberrant expression affects prognosis; 3) interphase cytogenetics, utilizing fluorescence in situ hybridization to evaluate the role of cytogenetic abnormalities in breast cancer prognostication; and 4) stromal-epithelial interactions, testing the hypothesis that cancer-derived stromal fibroblasts contribute to breast cancer invasiveness via overproduction of the extracellular matrix component, hyaluronic acid. The Program's Clinical Core will continue to provide the projects and the other cores with surgical breast specimens and fine needle aspiration material, to conduct the clinical protocols and in association with the Administrative Core to provide clinical data and prospective follow-up information on all patients whose tumor samples are being analyzed. The Immunopathology Core will optimize immunohistochemical assays and evaluate the prognostic significance of various cellular antigens. The Cell Culture Core will continue to process and bank dissociated breast tissue specimens, and provide cultured cells for the research projects. The Cytometry and Biostatistics Core will continue to provide biostatistical support, to maintain a database of all relevant data, and to perform cytometric and cytokinetic analyses. These molecular and cellular studies will be used to optimize and augment the routine assays being performed on biopsy material. The results from these studies will impact on breast cancer survival by improving prognostic indicators, as well as by providing new scientific insights into breast cancer pathophysiology.